Bis-chromone compounds

ABSTRACT

Compounds of the formula   The compounds are intermediates in the production of compounds useful as inhibitors of certain antigen-antibody reactions.   WHEREIN W represents carboxylic acid or functional derivatives or groups convertible thereto, with the proviso that YZ and Y&#39;&#39;Z&#39;&#39; are not both simultaneously the chain   WHEREIN R1, R2, R3, R4, R5 and R6 are each selected from hydrogen, halogen, hydroxy, lower alkyl, lower alkoxy, hydroxy lower alkyl, halo lower alkyl, hydroxy lower alkoxy and lower alkoxy lower alkoxy, X is selected from straight and branched, saturated and unsaturated hydrocarbon chains which are uninterrupted or interrupted by a member from the group of benzene, oxygen, and carbonyl and are unsubstituted or substituted by a member of the group of halogen, hydroxy and lower alkoxy, and YZ and Y&#39;&#39;Z&#39;&#39; are selected from

United States Patent Fitzmaurice et al.

[451 Jan. 21, 1975 l l BlS-CHROMONE COMPOUNDS 175] inventors: Colin Fitzmaurice, Macclesfield;

Thomas Brian Lee, Loughborough, both of England [73] Assignee: Fison House, London, England [22] Filed: July 19, 1972 [21] Appl. No.: 273,169

Related US. Application Data [60] Continuation-impart of Ser. No. 762,638, Sept. 25, 1968, Pat, No. 3,686,320, which is a division of Ser. No. 536,281, March 22, 1966, Pat. No. 3,419,578.

[30] Foreign Application Priority Data Primary ExaminerHenry R. Jiles Assistant Examiner-S. D. Winters Attorney, Agent, or Firm-Wenderoth, Lind & Ponack [57] ABSTRACT Compounds of the formula YZ O X O wherein R, R R, R, R and R are each selected from hydrogen, halogen, hydroxy, lower alkyl, lower alkoxy, hydroxy lower alkyl, halo lower alkyl, hydroxy lower alkoxy and lower alkoxy lower alkoxy,

X is selected from straight and branched, saturated and unsaturated hydrocarbon chains which are uninterrupted or interrupted by a member from the group of benzene, oxygen, and carbonyl and are unsubstituted or substituted by a member of the group of halogen, hydroxy and lower alkoxy, and Y2 and Y'Z' are selected from wherein W represents carboxylic acid or functional derivatives or groups convertible thereto, with the proviso that Y2 and Y'Z' are not both simultaneously the chain The compounds are intermediates in the production of compounds useful as inhibitors of certain antigenantibody reactions.

4 Claims, N0 Drawings BIS-CHROMONE COMPOUNDS Pat. No. 3,686,320 which application is a division of 5 application Ser. No. 536,281 filed Mar. 22, 1966, now US. Pat. No. 3,419,578.

This invention is concerned with improvements in or relating to new chemical compounds and pharmaceutical compositions containing them.

it has now been found that certain new chromone dc rivatives, as hereinafter defined, possess special activity as inhibitors of the effects of certain types of antigenantibody reaction, as evidenced, for example, by in vivo tests,

According to the invention, therefore, there are provided as new compounds bis-chromonyl compounds of the formula:

0 ll R1 R4 l l l l l 1102c 0011 R2 R3 R5 R6 and functional derivatives thereof, in which R, R R, R, R and R are the same or different and each is a hydrogen or halogen atom (e.g., a chlorine, bromine, iodine or fluorine atom), a lower alkyl (e.g., a methyl, ethyl, propyl, isopropyl, butyl or tertiaryl butyl group), hydroxy, lower alkoxy (e.g., a methoxy, ethoxy, propoxy. isopropoxy, butoxy or tertiary butoxy group). or substituted lower alkyl or lower alkoxy group, (for example a hydroxyloweralkoxy, loweralkoxyloweralkoxy, carboxyloweralkoxy, hydroxyloweralkyl or haloloweralkyl such as ehloro-, bromo-, iodo' or fluoroloweralkyl) and X is a saturated or unsaturated, substituted or unsubstituted, straight or branched polymethylene chain which may be interrupted by one or more carbocyclic rings or oxygen containing heterocyclic rings, (e.g., benzene, dioxan, tetrahydrofuran, or dihydropyran rings), oxygen atoms or carbonyl groups.

In general, it is preferred that not more than one of R R and R and not more than one of R*, R and R is other than hydrogen.

Accordingly a preferred embodiment of the invention is constituted by bis-chromonyl compounds of the formula:

R R l l l m 1102C 0 O COZH and functional derivatives thereof, in which X has the meaning defined above.

The group X may be any of a wide variety of groups. Thus for example, it may be a straight or branched saturated or unsaturated hydrocarbon chain. Further, X may be such a chain interrupted by one or more oxygen atoms, carbonyl groups or carbocyclic or heteroeyclic rings and may be substituted by one or more halogen atoms (e.g., chlorine, bromine, iodine or fluorine atoms), or hydroxy or lower alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert.butoxy, etc) groups. Specific examples ofthe group X are groups of the formulae:

W-cmst 2 /O 00211 fl i Y)? on H OH (l /'K th and its functional derivatives.

Functional derivatives of the compounds according to the invention include salts, esters and amides of one or more of the carboxylic acid functions present and esters of any hydroxylic functions present.

Salts of the bis-chromonyl compounds which may be mentioned are salts with physiologically acceptable cations, for example, ammonium salts, metal salts such as alkali metal salts (e.g., sodium, potassium and lithium salts) and alkaline earth metal salts (e.g., magnesium and calcium salts) and salts with organic bases, e.g., amine salts such as piperidine, triethanolamine and diethylaminoethylamine salts.

Esters which may be mentioned include simple alkyl esters (e.g., methyl, ethyl, propyl, isopropyl, butyl and tertiary butyl esters) and amides which may be mentioned include simple amides (for example amides with ammonia and lower alkylamines such as methylamine, ethylamine, etc.) and more complex amides with amino acids such as glycine.

The new bis-chromonyl compounds according to the invention have been shown to inhibit the release and/or action of toxic products which arise from the combination of certain types of anitbody and specific antigen, e.g., the combination of reaginic antibody with specific antigen. In man, it has been found that both subjective and objective changes which result from the inhalation of specific antigen by sensitised subjects are markedly inhibited by prior administration of the new bischromonyl compounds. Thus the new compounds are of great value in the prophylactic treatment ofextrinsic" allergic asthma. It has also been found that the new bis-chromonyl compounds are of value in the prophylactic treatment of so-called intrinsic asthma (in which no sensitivity to extrinsic antigen can be demonstrated).

It has also been found that in certain virus/antibody neutralisation systems the new bis-chromonyl compounds enhance the neutralising capacity of the antiserum, and thus the new compounds may find use in the treatment of viral infections.

According to a further feature of the invention, therefore, there is provided a pharmaceutical composition comprising a bis-chromonyl compound according to the invention, preferably in the form ofa salt, in association with a pharmaceutical carrier or diluent. There is also provided a process for the manufacture of a pharmaceutical composition which comprises mixing a bis-chromonyl compound with a carrier or diluent.

The nature of the composition and the pharmaceutical carrier or diluent will, of course, depend upon the desired route of administration, i.e., orally, parenterally or by inhalation.

The compositions according to the invention are especially useful for the prophylactic treatment of asthma, i.e., the compositions are administered to the patient at regular intervals (e.g., 4-6 hourly) in order to inhibit the effects of asthmatic attacks from which the patient may suffer. When employed in this manner, the dosage of composition is preferably such that from 1-50 mg. of active compound are administered to the patient at each administration.

In general, for the prophylactic treatment of asthma, the compositions will be in a form suitable for administration by inhalation. Thus the compositions may comprise a suspension or solution of the active ingredient in water for administration by means ofa conventional nebulizer. Alternatively the compositions may comprise a suspension or solution of the active ingredient in a conventional liquified propellant such as dichlorodifluoromethane or chlorotrifluorethane to be administered from a pressurised container. The compositions may also comprise the solid active ingredient diluted with a solid diluent, e.g., lactose, for administration from a powder inhalation device.

The pharmaceutical compositions according to the invention generally contain a minor proportion of bischromonyl compound and a major proportion of carrier or diluent. Thus, for example, the solutions for administation by a conventional nebuliser will comprise a dilute solution, e.g., about 0.5 percent, in sterile water, and compositions comprising suspensions or solutions in pressurised propellants will contain, for example, about 2 percent of the active bis-chromonyl compound. However, where the composition comprises the solid bis-chromonyl compound diluted with a solid diluent, the diluent may be present in less, equal or greater amount than the solid active ingredient, for example the diluent may be present in an amount of from 50 to percent by weight of the solid active ingredient.

The invention also includes within its scope a method of inhibiting the effects of the antigen-antibody reaction which comprises the prior application to the area of the antigen-antibody mechanism a therapeutically effective amount of a bis-chromonyl compound according to the invention.

According to a particular embodiment, the invention is for a method of relieving or preventing allergic airway obstruction which comprises administering to the patient a therapeutically effective amount (e.g., l-50 mg) at suitable intervals of a bis-chromonyl compound according to the invention, particularly in the form of a salt.

The new compounds according to the invention are prepared by linking together two chromone-2- carboxylic acids or precursors therefor.

According to a further feature of the invention, therefore, there is provided a process for the preparation of bis-chromonyl compounds of the formula:

and functional derivatives thereof, in which R, R R, R, R and R have the meanings defined above, which comprises reacting in one or more stages,

a. a compound of the formula:

b. a compound of the formula:

and

c. a compound of the formula:

in which Z is a hydroxy group and Y is a hydrogen atom, a group COCH or a group COOR (in which R is an alkyl group), or Y and 2 together form a chain or a chain (in which W is a carboxylic acid group or a functional derivative thereof or a group convertible to a carboxylic acid group or a functional derivative thereof), Y and Z have the same definition as Y and Z above and may be the same or different; and A and B are the same or different and each is a group capable of reacting with a hydroxyl group to form an ether linkage, or one of A and B is a group capable of being converted to such a reactive group; and X is such that the group A'X--B (in which A and B are the residues of A and B after the formation of ether linkages) has the same meaning as X; to form a compound of the forand, ir'ncsai'y,"fii'tkrhtdi'fay or subsequently converting Y and Z and/or Y and Z to chains of the formula COCH=C(COOH)O-, or functional derivatives thereof.

As stated above, the process according to the invention may be carried out in one or more stages. Thus, it may be carried out in two stages as follows:

This procedure will generally be adopted when the two chromone moieties ofthe desired bis-chromonyl compound are different, i.e., when R, R and R" are different from R, R and R. In the two stage process, the groupings Y and Z or Y and Z may be modified at an intermediate stage but. in general, it is not preferred to follow this route. When the two chromone moieties of the desired bis-chromonyl compound are the same the reaction may be carried out in two stages. or preferably, if Y' and 2 have the same meanings as Y and Z. in one stage. i.e.. by reaction ofa compound ofthe formula:

with a compound of the formula:

A X B When the reaction is carried out in two stages the compound A-XB may be such that one of A and B is a group capable of being converted to an ether linkage forming group. When both A and B are ether linkage forming groups, the first stage of a two stage reaction will, of course, be carried out using substantially equimolecular proportions of the two compounds.

Examples of groups A and B capable of reacting with a phenolic hydroxyl group, such that an ether linkage is formed by X and the hydroxyl group, include halogen atoms, e.g., chlorine, bromine or iodine atoms, or other anion forming groups such as tosylate or methane sulphonate groups. Where the group A contains a hydroxy group beta to the subsequently formed ether linkage the group A or B may represent an epoxide group, giving rise to a residue A or B of CH CHOH. The groups A and B may be the same or different; thus a compound A-XB capable ofyielding a Z-hydroxy-trimethylene linkage is the compound:

Groups capable of being converted to reactive groups such that an ether linkage may be subsequently formed include hydroxyl groups which may be converted to halogen suhstituents or other anion forming groups such as tosylate or methane sulphonate. The group A or B may alternatively be a vinyl group (CH=CH which may subsequently be converted to an epoxide or halohydrin group. Thus, an example of a compound AXB which may be used to produce a Z-hydroxy-trimethylene linkage is allyl bromide.

The reaction between the chromone moiety or precursor therefor and the linking compound A-X'-B will be carried out under the conditions normally employed for the formation of ether linkages. Thus, the reaction will generally be carried out in the presence of aqueous alkali or a solvent such as acetone or dioxan and at elevated temperature. Where the ether linkage formation is carried out by reaction of the aromatic hydroxy group and a compound AX--B in which A and/or B is an anion forming group (e.g., halogen, methanesulphonate. etc.) the reaction is desirably carried out in the presence of an acid binding agent such as an alkali metal carbonate (e.g., sodium carbonate or potassium carbonate) or an organic acid binding agent such as pyridine, diethylaniline or triethylamine. Where A and/or B is an epoxide group the ether forming reaction may be conveniently carried out in the presence of a suitable catalyst, e.g., in the presence of a quaternary ammonium hydroxide.

The conversion, if necessary, of Y and Z and/or Y and Z to the desired chain CO-CH=C(COOH- )--O or functional derivative thereof will be carried out simultaneously if Y and Z are the same as Y and Z and in separate stages if y and Z are not the same as Y and Z. It is, however, generally preferred that Y and Z are the same as Y and Z since this reduces the number of chemical stages involved.

In the following description of methods ofconverting Y and Z to the desired chain CO-CH=C(COOH- )O or functional derivatives thereof reference will only be made to one chromone moiety but it' will, of course, be understood that where Y and Z are the same as Y and Z the process will act simultaneously on both moieties.

A preferred process involves the conversion of the compound in which Y is a group COCH and Z is a hydroxy group (i.e., a substituted hydroxyacetophone) to a chain CO-CH=C(COOR- )O (in which R is a hydrogen atom or an alkyl This reaction may be carried out by a number of routes. A preferred route involves the reaction of the o-hydroxyacetophenone with an oxalic acid derivative of the formula:

in which R is a halogen atom or a group OR (in which R is an alkyl group), R" and R are both halogen atoms and R is a group OR or R and R towhere R is the alkyl group of the dialkyl oxalate, which intermediate may be cyclised directly by heating or may be isolated and cyclised by heating in a suitable solvent in the presence ofa cyclisation agent such as an acid.

When the oxalic acid derivative is of the formula:

R'OC(Hal)-,-COOR in which R is an alkyl group. e.g., ethyl ethoxydichloroacetate, the reactants are desirably employed in substantially equimolecular proportions and the reaction is conveniently carried out in the presence of a metallic catalyst such as finely divided metallic platinum. palladium or ruthonium. When the oxalic acid derivative is of the formula:

Hal CO COOR CII I I ll (ill-LC 02R which may then be oxidatively cyclised to the desired chromone-Z-carboxylic acid. Non-oxidative cyclisation gives rise to the corresponding chromanone which may be converted to the chromone as described below.

A different route for the formation of the desired chromonyl compound involves the conversion of Y and Z (when Y is COCH and Z is OH) to an intermediate of the formula:

in which V is a group convertible to a carboxylic acid, or functional derivative thereof, and subsequent conversion of the group V to a carboxylic acid group or functional derivative thereof.

Examples of the group V are the nitrile group which may be hydrolysed to a carboxylic acid group and groups such as methyl, hydroxymethyl, halomethyl (e.g., chloromethyl, bromomethyl, dichloromethyl, trichloromethyl), formyl, acetyl, vinyl and styryl groups, oxidisable or hydrolysable to a carboxylic acid group.

The Z-methyl chromone may be prepared from the o-hydroxyacetophenone by condensation with an alkyl acetate, in a similar manner to the condensation described above for the dialkyl oxalate.

The 2-methyl chromone also serves as an intermediate in the preparation of a number of other oxidisable derivatives. Thus, the Z-methyl chromone may be converted into the corresponding 2-halomethyl-chromone, e.g., by reaction with hydrogen chloride and manganese dioxide in boiling acetic acid to produce a 2- chloromethyl chromone or by reaction with bromine in acetic acid to yield the 2-bromomethylchromonc. The 2-halomethyl chromone may be oxidised to the corresponding chromone-Z-carboxylic aicd, for example. with potassium permanganate. or may be hydrolysed. using, for example, moist silver oxide, to give the 2- hydroxymethyl chromone which may then be oxidised to the chromone-Z-carboxylic acid, for example, using chromium trioxide as oxidising agent in the presence of acetic acid and at ambient temperature or below.

The Z-methyl chromone may further be reacted with p-nitrosodimethylaniline and the reaction product hydrolysed with dilute mineral acid to give the corresponding 2-formyl-chromone which may be oxidised to the corresponding chromone-Z-carboxylic acid using, for example, chromium trioxide as reagent.

Condensation of the Z-methyl-chromone with a benzaldehyde in the presence of a condensation catalyst gives the 2-styryl chromone which may be oxidised to the corresponding chromone-Z-carboxylic acid, for example using potassium permanganate.

A number of the chromone derivatives, other than the 2-methyl chromone, convertible to the chromone- 2-carboxylic acid may be prepared directly from the o-hydroxy-acetophenone.

Thus, the 2-formyl chromone may be prepared by condensation of a dialkoxy acetate of the formula:

in which R and R" have the meanings defined above, e.g., ethyl diethoxy acetate, with the o-hydroxyacetophenone to yield an acetal which may subsequently be hydrolysed, e.g., with dilute mineral acid, to the aldehyde, which may subsequently be oxidised to the carboxylic acid.

The 2-formyl chromone may also serve a starting point for the preparation of the 2-cyanon chromone. Thus, the 2-formyl chromone may be reacted with hydroxylamine to yield the 2-oximino-chromone which may then be dehydrated to the 2-cyanochromone which may then be hydrolysed to the chromone-2- carboxylic acid or amide thereof under acid conditions.

The 2-styryl chromone may be prepared from the ohydroxy-acetophenone by reaction with sodium cinnamate and cinnamie anhydride (i.e., by the Kostanecki reaction) or by reaction with a cinnamoyl halide, e.g. cinnamoyl chloride, in the presence of an acid binding agent to yield the cinnamate ester of the o-hydroxyacetophenone followed by treatment with a base, e.g., potassium carbonate, in the presence of an inert solvent such as toluene or benzene to give an alphadiketone of the formula:

10 which is subsequently cyclised either by direct heating or by heating in the presence of a cyclisation agent (Baker Venkataraman reaction).

The 2vinyl chromone may likewise be prepared from the o-hydroxy-acetophenone by reaction with ethyl acrylate.

The compound in which Y is a hydrogen atom and Z is a hydroxyl group, i.e., the phenol of the formula:

may be converted to the corresponding chromone-2- carboxylic acid by a number of methods.

For example, the chromone-Z-carboxylic acid may be prepared by reaction of acetylene dicarboxylic acid or a dialkyl ester thereof, e.g., diethyl acetylene dicarboxylate, with the phenol or with an alkali metal phenate thereof.

Where the acetylene dicarboxylic acid or ester thereof is reacted with the alkali metal phenate, i.e., the compound of the formula:

in which M is an alkali metal atom, the reaction is desirably carried out in the presence of an inert organic solvent or diluent to yield a fumarate of the formula:

which is then, if necessary after hydrolysis, cyclised to the desired chromone-2-carboxylic acid, for example by heating in the pressure of a cyclisation catalyst such as sulphuric acid. In a modification of this process the acetylene dicarboxylic acid or ester thereof is replaced by a halo-fumaric acid or an ester thereof, e.g., diethyl chlorofumarate, or by a dihalosuccinic acid or ester thereof.

The chromone-2-carb0xylic acid may also be prepared from the phenol by reaction with a compound such as ethyl ethoxalylacetate.

In another method the phenol may be esterified, e.g., with ethyl ethoxalyl chloride to give an ester of the formula:

OzClJOzEt which may subsequently by cyclised in the presence of acetic acid or a derivative thereof (e.g., ethyl acetate or acetyl chloride) to give the desired chromone-2- carboxylic acid.

The phenol may alternatively be condensed with maleic anhydride to give a compound of the formula:

C11 OXO i g OH H. 002R which may then be oxidatively cyclised to the desired chromone-Z-carboxylic acid. Non-oxidative cyclisation gives rise to the corresponding chromanone which may then be converted to the chromone as described below.

The compound in which Z is a hydroxyl group and Y is a group COOR i.e., the substituted salicyclic acid ester of the formula:

may be converted to the desired chromone-2- carboxylic acid by reaction with a pyruvate ester of the formula:

CH CO COOR if desired in the presence of a condensation agent such as an alkali metal alkoxide (e.g., sodium ethoxide), sodamide, metallic sodium or sodium hydride, and preferably in the presence of an organic solvent such as ethanol or dioxan.

When Y and Z together form a chain i.e., a chromanone, the group W will remain unchanged or be converted to a carboxylic acid group as necessary and further the chromanone will need to be dehydrogenated to the corresponding chromone; which dehydrogenation may be carried out either before or after any conversion of W.

The dehydrogenation of the chromanone of the formula:

may, for example, be effected using selenium dioxide or other suitable dehydrogenating agents such as palladium black or chloranil.

Alternatively, dehydrogenation may be carried out by bromination followed by dehydrobromination. Thus, the chromanone may be brominated using N- bromosuccinimide in an inert solvent or by treatment with pyridinium perbromide in an inert solvent such as chloroform in the presence of a free radical catalyst such as benzoyl peroxide. to yield the 3-bromo derivative which may be subsequently dehydrobrominated.

The processes described above generally lead to the formation of the chromone-Z-carboxylic acids as such or in the form of their esters. These may be readily converted to other functional derivatives, e.g., salts or amides, by conventional methods.

The majority of the intermediates produced by the linking of the two chromone moieties or precursors therefor are in themselves new.

According to the invention, therefore, there are provided as new compounds, compounds of the formula:

in which R, R R, R R R, X, Y, Z, Y and Z have the meanings defined above, provided that not more than one of Y and Z and Y and Z represents a chain COCH=C(COOH)O or a functional derivative thereof and further provided that when R, R R, R, R and R are hydrogen and Y and Y are groups COCH and Z and Z are hydroxyl groups, X is not a group CH --CHOH-CH linking the two positions para to the groups Y and Y.

This invention also provides a process for the preparation of the new intermediates which comprises reacting in one or more stages:

a. a compound of the formula:

b. a compound of the formula:

in which A and B have the meanings defined above.

In order that the invention may be well understood, the following examples are given by way of illustration only.

EXAMPLE 1 a. l,3-Bis(2-acetyl-3-hydroxyphenoxy)propane A mixture of 30.4 parts 2,6-dihydroxyacetophenone, 20.2 parts of 1,3-dibromopropane and 12.8 parts powdered potassium carbonate were heated under reflux in 200 parts by volume of acetone for 72 hours. The acetone solution was filtered and the solid residue was washed first with acetone and then with water. The combined acetone filtrate and washings were evaporated leaving an oil which, on being boiled with ether. gave pale yellow crystals. These were combined with the first obtained solid and extracted with refluxing isopropanol in a Soxhlet extractor for several days to obtain 16.1 parts of 1,3-bis(2-acetyl-3-hydroxyphenoxy) propane as almost colourless crystals melting between 184 and 185C.

Analysis:

Found: C. 65.4; H, 5.68%

CWHWO requires: C, 66.2; H. 5.81%

b. Diethyl ester of l,3-bis(2-carboxychromon- 5yloxy)propane A solution of 6.9 parts 1,3-bis(2-acety1-3- hydroxyphenoxy) propane in parts by volume of diethyl oxalate was added to a solution of 3 parts sodium in 30 parts by volume of ethanol and 50 parts by volume of benzene and the mixture was heated gently under reflux for hours. It was then poured into a large volume of ether and the precipitated solid was filtered, washed with ether and dried. It was then dissolved in water and acidified to obtain a sticky solid. This was boiled with about 50 parts ofethanol containing a catalytic amount of hydrochloric acid for about 10 minutes, when crystals began to form. The solution was cooled and filtered to obtain 7.4 parts of solid melting between 178 and 180C. This was recrystallised from 200 parts by volume of a 1:2 mixture of benzene and ethanol to obtain a first crop of 4.5 parts of the diethyl ester of 1,3-bis( 2-carboxychromon-5- y1oxy)propane, melting between 182 and 183C.

Analysis: Found: C. 63.2 H, 4.60% C H O requires: C. 63.7 H. 4.72%

Analysis: Found: c H Na O H O requires:

EXAMPLE 2 a 1,3-Bis( 2-acetyl-3-hydroxyphenoxy)-2- hydroxypropane By the method of Example 1 (a) 10 parts of 2,6- dihydroxyacetophenone, 4.6 parts potassium carbonate and 7.15 parts 1,3-dibromopropan-2-ol were reacted in acetone to obtain 3 parts of pure 1.3-bis(2- acetyl3-hydroxyphenoxy)-2-hydroxypropane as colourless crystals melting between 165 and 166C.

Analysis:

dihydroxyacetophenone and 325 parts of epichlorohydrin in 2.500 parts of hot isopropanol was added, with stirring under reflux, a solution of 233 parts of KOH in 2,500 parts of isopropanol and sufficient water (ca. parts) to dissolve the solid. The mixture was heated, with stirring, under reflux for 48 hours. Half the solvent was then distilled off and 5,000 parts of water were added. The mixture was cooled and the solid filtered off and washed with isopropanol and ether. It was the recrystallised from 12,500 parts of isopropanol to obtain a first crop of 380 parts of a second crop, after concentration, of 300 parts of 1,3-bis(2-acetyl-3- hydroxyphenoxy)-2-hydroxypropane identical with that obtained in Example 2 (a) above. c. Diethyl ester of 1,3-bis(2-carboxychromon-S-yloxy 2-hydroxypropane By the method of Example 1 (b) 4.6 parts of 1,3- bis(2-acetyl-3-hydroxyphenoxy)-2-hydroxypropane were reacted with diethyl oxalate and the product cy clised to obtain 4.4 parts of pure diethyl ester of 1,3- bis(Z-carboxychromon-5-yloxy)-2-hydroxypropane as pale yellow crystals melting between and 182 from a mixture of benzene and petrol.

Analysis: Found: 0.61.5; H, 4.61% C- H O requires: C. 61.8; H. 4.57%

1,3-bis( 2-carboxychromon-5- Analysis: C, H, Na, Found: 47.8; 3. 7.7% C H Na O 4H O requires: 47.3; 3.79; 7.7/1

e. l,3-Bis(2-carboxychromon-5-y1oxy)-2- hydroxypropane A solution of the disodium salt of l,3-bis(2- carboxychromon-S-yloxy)J-hydroxypropane in water 15 was acidified and the precipitate was recrystallised from ethanol plus ether to obtain l,3-bis(2- carboxychromon-S-yloxy)-2-hydroxypropane monohydrate as colourless crystals melting with decomposition between 216 and 217.

Analysis: Found: C. 56.7; H. 3.44% C H O H O requires: C. 56.8: H. 3.70%

salt. The mixture was cooled and filtered, and the solid was washed with cold water and dried at 110C.

Analysis:

Found: Ca, 7.19/1

C -,H, CaO,,3H O requires: Cu, 7.14%

g. Magnesium salt of l,3-bis(Z-carboxychromon-S- yloxy)-2-hydroxypropane A suspension of 2 parts of l,3-bis(2- carboxychromon-S-yloxy)-2-hydroxypropane in 20 dipiperidine salt of l,3-bis(2-carboxychromon-5- yloxy)-2-hydroxypropane.

Analysis: C. H. N.

Found: 59.0; 6.12: 4.00%

c,,,H,,No,..2H.o requires: 59.1; 5.67; 4.18%

EXAMPLE 3 a. 1,4-Bis( 2-acetyl-3-hydroxyphenoxy )but-2-ene By the method of Example 1 (a), 15.2 parts of 2,6- dihydroxyacetophenone were condensed with 10.7 parts of 1,4-dibrombut-2-ene to obtain 6 parts of 1,4- bis(2-acetyl-3-hydroxyphenoxy)but-2-ene melting between 145 and 146 from acetone. b. l.4-Bis(2-earboxychromon-S-yloxy)but-2-ene By the method of Example 1 (b). parts of l.4-bis(2- acetyl-3-hydroxyphenoxy)but-2-ene were condensed with diethyl oxalate to obtain 3 parts of the diethyl 16 ester of 1,4-bis(2-carboxychromon-5-yloxy)but-Z-ene as yellow crystals melting between 215 and 217C from ethanol.

Analysis: Found: C, 64.1: H. 4.69% C H O requires: C, 64.6; H, 411% Saponification of 2 parts of the diethyl ester of 1.4- bis-(2-carboxychromon-5-yloxy)but-Z-enc by the method of Example 1 (c) gave 1.5 parts of the disodium salt.

Acidification of an aqueous solution of this sodium salt gave the free acid monohydrate, melting between 193 and 195.

Analysis: Found: C. 59.6; H, 3.56% C H O H O requires: C, 59.7; H, 3.737!

EXAMPLE 4 l,l2-bis(2-carboxychromon-5-yloxy) 2,l l-dihydroxy 4,9-dioxadodecane A solution of 10 parts 2,6-dihydroxyacetophenone. 5.6 parts butane-1,4-diol diglycidyl ether and 0.1 part of 40 percent aqueous solution of benzyltrimethylammonium hydroxide in 14 parts dioxan was heated at 100C in a sealed vessel for 60 hours. The dioxan was removed under reduced pressure leaving a thick yellow oil. This was extracted several times with boiling ether and the combined extracts were fractionally precipitated with petrol. The first fraction, which was about 5 parts of a clear yellow oil, could not be crystallized or distilled but had an infra-red spectrum consistent with that expected for 1,1 2-bis( 2-acetyl-3- hydroxyphenoxy)-2,l l-dihydroxy-4,9-dioxadodecane. This was condensed with diethyl oxalate by the method of Example 1 (b) to obtain 3 parts of the diethyl ester of 1,12-bis(2-carboxychromon-5-yloxy)-2,l ldihydroxy-4,9-dioxadodecane as an oil. This oil was stirred and warmed with a saturated aqueous solution of sodium bicarbonate until dissolved. The solution was filtered and acidified with dilute hydrochloric acid. The precipitate was dissolved in ethanol plus ethyl acetate, treated with charcoal, filtered and precipitated with petrol and the solid was recrystallised from acetone plus ether to obtain 1 part of pure l,l2-bis(2- carboxychromon-S-yloxy)-2,1 l-dihydroxy-4,9- dioxadodecane dihydrate as colourless crystals melting with decomposition at C.

Analysis: Found: C, 55 3 H, 5 2471 C, .H -,,,O, ,2H O requires: C. 55 3 H. 5 22% Analysis: Found: C. C, ,H ,.Na O 4H requires: C.

EXAMPLE a. 1,4-Bis(2-acetyl-3-hydroxyphenoxy)butane By the method of Example 1 (a) 2.6- dihydroxyacetophenone was reacted with 1,4- dibromobutane to obtain l,4-bis(2-acetyl-3-hydroxyphenoxy)butane melting between 219 and 221C from benzene.

Analysis: Found: C, 66.0; H, 60% C H O. requires: C. 67.0; H. 6.2 /1

b. Diethyl ester of l,4-bis(2-carboxychromon-5- yloxy)butane By the method of Example 1 (b) l,4-bis(2-aceteyl-3- hydroxyphenoxy)butane was condensed with diethyl oxalate to form the diethyl ester of 1,4-bi5(2- carboxychromon-S-yloxy)butane melting between 195 and 199C from a mixture of ethyl acetate and isopropanol.

Analysis: Found: C. 62.4; H, 5.l'/1 C H O H O requires: C. 62.3; H, 5.2

Analysis: Found:

561.6; C H O H O requires: 5;

This acid was dissolved in an equivalent amount of sodium bicarbonate solution and freeze-dried to obtain the disodium salt.

EXAMPLE 6 l,5-Bis(2-carboxychromon-5-yloxy)pentane 2,6-Dihydroxyacetophenone was reacted with 1,5- dibromopentane as in Example 1(a) to obtain 1.5- bis(2-acetyl3-hydroxyphenoxy) pentane melting between l3l and 133C from benzene.

Analysis: Found: C. 674; H 6.3% H- 0 requires: C, 67.7; H 6.5%

This diketone was condensed with diethyl oxalate as in Example l(b) to obtain the diethyl ester of 1.5-bis( 2- carboxychromon-5-yloxy)pentane, melting between and 152C from ethanol.

Analysis: Found: C, 64.6; H. 5.3% C H O requires: C. 64.8; H, 5.361

The ester was hydrolysed as in Example 5(c) to obtain the acid a monohydrate melting between 226 and 228C from ethanol.

Analysis: Found: C, 60.3; H, 4.7% C ,,H .,O,.,H O requires: C, 60.2; H. 4.4%

The acid was subsequently converted to the disodium salt by the method of Example 5(c).

EXAMPLE 7 1,6-Bis( 2-carboxychromon-5-yloxy)hexane 2,6-Dihydroxyacetophenone was reacted with 1,6- dibromohexane as in Example 1(a) to obtain l,6-bis(2- acetyI-S-hydroxyphenoxy) hexane melting between 147.5 and 148.5C from ethanol.

Analysis: Found: C, 68.1, H, 6.7% C H- O requires: C, 68. H. 6.8%

This diketone was condensed with diethyl oxalate by the method of Example 1(b) to obtain the diethyl ester of 1,6-bis (2-carboxychromon-5-yloxy)hexane melting between 154.5 and 155C from ethanol.

Analysis: Found: C, 65.0; H, 5.4% C H O requires: C. 65.4; H, 5.5%

The ester was hydrolysed as in Example 5(c) to obtain the acid monohydrate melting between 228 and 230C from dioxan.

Analysis: Found: C. )2; H. 4.9% C- H O H O requires: C. 1.9; H, 4.7%

The disodium salt of the acid was subsequently prepared as in Example 5 (c).

EXAMPlE 8 l.l0Bis(2-carboxychromon-S-yloxy)decane 2.6-Dihydroxyacetophenone was condensed with 1.10-dibromodecane as in Example 1 (a) to obtain 1,1- 0-bis(2-acetyl-3-hydroxyphenoxy) decane melting between l02.5 and 104C from ethyl acetate.

Analysis: Found: C, 70.0, H. 7.4% C H O requires: C, 70.6: H, 7.7%

This diketone was reacted with diethyl oxalate as in Example 1 (b) to obtain the diethyl ester of 1,10-bis(2- carboxychromon-S-yloxy)decane melting between 146.5 and 148C from ethanol plus dioxan.

Analysis: Found: C, 67.4, H, 6.45% C H O requires: C, 67.3, H, 6.3%

The ester was hydrolysed by boiling with aqueous sodium bicarbonate to obtain the sparingly soluble disodium salt which was recrystallised from water.

Analysis: Found: C, 63.5; H, 5.1 /1 C H O requires: C, 64.1; H, 5.901

This was condensed with diethyl oxalate as in Example 1 (b) to obtain the dicthyl ester of 1,5-bis(2- carboxychromon-S-yloxy)-3-oxapentane melting between 129 and 131.5C front methanol.

Analysis: Found: C. 62.3. H. 4.90; C H O requires: C, 62.4: H, 4.9%;

The ester was hydrolysed as in Example 5 (e) to obtain the acid melting between 219 and 220C from ethanol plus dioxan.

Analysis: Analysi Found: C, 59.8 H, 3.9% Found: C. 61. H C H O requires: C, 59.8 H. 3.8% C:,H ,,Na Om requires: C, 60.6; H, 4.7'/!

The disodium salt of the acid was subsequently pre- EXAMPLE 9 pared as in Example 5 (c). l,7-Bis(2-carboxychromon-5-yloxy)-2,6-dihydroxy-4- EXAMPLE 1 l oxaheptane 1,4-Bis(2-carboxychromon-5-yloxy)-2,3-

2,-Dihydroxyacetophenone was reacted with diglycdih d b lClyl ether as in Example 4 H.) obtain 1,7-bis (2-acetyl-3- 2 6-Dihydroxyacetophenone was reacted with hydroxypherggxy) Z -d Y Y- v Q FQQ QZQX f l,2:3,4-bisepoxybutane as in Example 4 to obtain 1,4- oxaheptane melting between 129 and 131C from bis(2-acetyl-3-hydroxyphenoxy)-2,3-dihydroxybutane, ethyl acetate plus petrol. melting between 211 and 212C from dioxan.

Analysis: Analysis: Found: C, 60.4: H, 6.3% Found: C, 61.0 H, 5.7% C H O, requires: C, 60.8; H, 6.0% CZQHMOH requires: C, 61.5 H, 5.77!

p 4 4 This diketone was reacted with diethyl oxalate to ob- This was condensed wlth y Oxalate Examtain the bischromone diethyl ester as an oil which could P 1 (b) to Obtain the methyl ester of 1!4-b|$(2- not be crystallised. This ester was hydrolysed as in Excarboxychiomon'5'lgloxy)'z3'dlhydroxybumne ample 5 (c) to obtain 1,7-bis (2-carboxychromon-5- tween 224 and 226 yloxy)-2,6-dihydroxy-4-oxaheptane monohydrate melting between 216 and 218C.

Analysis: Found: C, 59.2 H, 4.671 C2-H2O,-, requires: C, 60.6. H, 4.7% Analysis: Found: I C, 55.6: H, 3.42/1 w u m z rcqulrcsl 55-7; This was hydrolysed by the method of Example 5 (c) to obtain the acid as a dihydrate melting between 260 and 262C. The dlSOdlUlTl salt was subsequently prepared as m Example 5 (c).

EXAMPLE 10 Analysis: F d: C, 54.0, H, 3.771 1,5-B|s(2-carboxychromon-5-yl0xy)-3-oxapentane Z J requires. C. 54.0.

2,6-Dihydroxyacetophenone was condensed with 2,2-dibromodiethy1 ether, as in Example 1 (a) to obtain l ,5-bis( 2-acetyl-3-hydroxyphenoxy)-3-oxapentane melting between 120.5 and 121.5C from methanol.

This was subsequently converted to the disodium salt as in Example 5 (c).

EXAMPLE 12 1,4-Bis(2-earboxychromon-5-yloxy)-2-hydroxybutane 2,6-Dihydroxyacetophenone was condensed with l-bromo-3,4-epoxybutane by boiling in acetone in presence of potassium carbonate to obtain l.4-bis(2- acetyl-3-hydroxyphenoxy)-2-hydroxybutane melting between 207.5 and 208.5C from methanol.

Analysis: Found: C. 63.4;

C H O requires: C, 64.2;

This was condensed with diethyl oxalate as in Example 1 (b) to obtain the diethyl ester of l,4-bis(2- carboxychromon-S-yloxy)-2-hydroxybutane melting between 216 and 217C from a mixture of chloroform, ethyl acetate and petrol.

Analysis: v Found: C, 62.7, H, 5.2/r C H O requires: C. 62.4 H, 4.9%

This was hydrolysed as in Example 5 (o) to obtain the acid as a monohydrate melting between 226 and 227C.

Analysis: Found: C, CMHIMOIIHZO requires:

This was subsequently converted to the disodium salt as in Example 5 EXAMPLE 13 1,5-Bis( 2-carboxychromon'7-yloxy)pentane Ethyl 7'hydroxychromone-2-carboxylate was condensed with one half equivalent of 1,5-dibromopentane by heating in acetone in presence of potassium carbonate to obtain the diethyl ester of l,5-bis(2- carboxychromon-7-yloxy)pentane melting between 148 and 150C from ethanol.

Analysis: Found: za ax m requires:

This ester was hydrolysed as in Example (c) to obtain the acid melting between 283 and 284C.

Analysis: Found: a -m requires:

ION

The acid was subsequently converted to the disodium salt by the method of Example 5 (c).

EXAMPLE l4 Analysis: Found: C,,. .H;,,,O,,, requires:

EXAMPLE 15 1,5-Bis(2-carboxy-8-chlorochromon-S-yloxy )pentane A mixture of 4.62 parts of l,5-bis(2-acetyl-3- hydroxypphenoxy) pentane (from Example 6) and 2.7 parts of sulphuryl chloride in 300 parts of dry ether was stirred for 7 hours at room temperature. The solution was filtered and evaporated to dryness leaving a yellow solid. This was recrystallised from ether to obtain 2.36 parts of 1,5-bis(2-acetyl-4-chlor0-3-hydroxyphenoxy)- pentane as pale yellow prisms melting at 96C.

This was condensed with diethyl oxalate as in Example l (b) to obtain the diethyl ester of l,5-bis(2- carboxy-8-chlorochromon-5'yloxy)pentane melting between 162 and 164C from ethanol.

Analysis: Found: C. 57.7; H. 4.3% C- H Cl- O requires: C. 57.5 H, 4.3

The ester was hydrolysed as in Example 5 (c) to obtain the acid, melting at 244C from ethanol.

Analysis: C, H Cl, Found: 542; 4.6; 12.9'7/ C ,,H Cl O requires: 54.7; 3.28; 12.9%

The acid was converted to the disodium salt by the method of Example 5 (c).

EXAMPLE 16 a. 2-(2,3-Epoxypropoxy )-6-hydroxyacetophenone To a mixture of 5.68 parts of 2,6-

dihydroxyacetophenone, 10.3 parts of epichlorohydrin and 3 parts (by volume) of ethanol which was stirred and gently refluxed, was added slowly a solution of 2.58 parts of potassium hydroxide in 7 parts (by volume) of ethanol and 1 part (by volume) of water. The mixture was then stirred and refluxed for 1 hour. then after cooling an excess of water was added and the product was extracted into ether and the solution was dried over sodium sulphate. After removing the drying agent and the solvent parts of a crude oil remained. This oil was extracted using hot petrol ether (b.p. 40-60) and on cooling yellow crystals of'2-(2.3-epoxypropoxy)-6- hydroxyacetophenone m.p. 61-63 separated.

Analysis: Found: C. 63.5 H. 5.7% CIIHIZO, requires: C. 63.4 H. .8%

b. 1-(2-Acety1-3-hydroxyphenoxy)-3-(4-acetyl-3- Analysis: Found: C. 62.8, H, 5.4// C H O requires: C, 63.3 H, 5.671

c 2-( 3-Chloro-2-hydroxypropoxy )-6- hydroxyacetophenone A mixture of 10 parts of 2,6-dihydroxyacetophenone, 7 parts of epichlorohydrin in 18 parts (by volume) of dioxan and 5 drops of Triton B, was heated at 100C in a sealed vessel for 2 /2 days. The solvent was then removed under reduced pressure and an excess of ether was added to the residue. The ether solution was decanted from the insoluble, washed with water (2 X 50 parts) and 2N sodium carbonate (3 X parts). The solvent was removed after drying over sodium sulphate and the residue was purified by chromatography using an alumina column and other as eluent. The oil was distilled to obtain 2-(3-ch1oro-2-hydroxypropoxy)-6- I hydroxyacetophenone (6 parts) as a yellow oil b.p.

Analysis: Found: C. 53.7; H, 5.26% C H CIO requires: C, 54.0; H, 5.32%

d. l-( 2-Acetyl-3-hydroxyphenoxy)-3-( 4-acety1-3- e. 1-(2-Ethoxycarbonylchromon-S-yloxy) 3-(2- ethoxycarbony1chromon-7-yloxy)-2-hydroxypropane.

By the method of Example 1(b) 1-(2-acetyl-3- hydroxyphenoxy)-3-(4-acetyl-3-hydroxyphenoxy)-2- hydroxypropane was condensed with diethyl oxalate to form l-( 2-athoxycarbonylchromon-S-yloxy )-3-( 2- cthoxycarbonylchromon-7-y1oxy)-2-hydroxypropane melting between 193 and 194.5C from ethanol plus dioxan.

Analysis: Found: C. 62.0. H. 4.3"; C H O requires: C. 61.8 H. 4.6";

f 1-( 2-Carboxychromon-5-y1oxy )-3-( 2- carboxychromon-7-y1oxy)-2-hydroxypropane.

The ester from (c) above was hydrolysed as in Example 5(c) to obtain the acid melting between 194 and 200C with preliminary softening.

Analysis:

Found: C. 55.2: H 3.96% C H O H O requires: C, 54.7; H "1.9%

This acid was dissolved in an equivalent amount of sodium bicarbonate solution and freeze-dried to obtain the disodium salt.

EXAMPLE 17 a. 1-( 2-Acety1-3-hydroxyphenoxy-5-( 4-acetyl-3- hydroxyphenoxy)pentane A mixture of 5.1 parts of 2,6- dihydroxyacetophenone, 7.7 parts of 1.5-

dibromopentane, and 2.3 parts of anhydrous potassium carbonate in parts (by volume) of anhydrous acetone was refluxed for 20 hrs. An examination of this mixture by thin layer chromotography showed unchanged 2,6-dihydroxy acetophenone, l,5-bis(2- acetyl-3-hydroxyphenoxy)pentane and suspected 2-(5- bromopentyloxy)-6-hydroxyacetophenone to be present. The acetone solution was concentrated to half its volume and the residue was removed by filtration. After washing with water this residue yielded 1.9 parts of 1,5-bis(2-acety1-3-hydroxyphenoxy)pentane. The filtrate was taken to dryness and chromatographed on an alumina column using ether as eluent. The 2-(5- bromopentyloxy)-6-hydroxyacetophenone came off in the first fractions, as confirmed by thin layer chromatography. Evaporation of these collected fractions yielded 5 parts as an oil which was used as follows without further purification. Thus a mixture of 2.4 parts of the crude oil, 1.2 parts of resacetophenone, 1 part of anhydrous potassium carbonate and 40 parts (by volume) of dry acetone was refluxed for 20 hrs. After cooling the acetone solution was filtered and evaporated to dryness. The residue was crystallised from methanol-water to yield 1.85 parts of l-(2-acety1-3- hydroxyphenoxy)-5-(4-acety1-3-hydroxyphenoxy)pentane melting between 91 and 91.5C.

Analysis: Found: C. 67.3; H. 6.77: t quires 11 H 6% Analysis; Found: C, 64.1; H. 5.3% C ,,H O requires: C. 64.9; H. 5.3%

c. 1-( 2-Carboxychromon-5-yloxy)-5-(2- carboxychromon-7-yloxy)pentane To 1.0012 parts of the above bis-ester in 30 parts (by volume) of methanol was added an amount of 0.969N sodium hydroxide in methanol just sufficient for the ester hydrolysis. This mixture was then heated on the steam-bath for /2 hr, the solvent was distilled off and the residue was taken up in water and filtered, the filtrate was then acidified with dilute hydrochloric acid. The solid which separated proved difficult to filter and was, therefore, separated from the liquors by centrifuging, washing twice with water and recentrifuging. The 1-( 2-carboxychromon-5-yloxy)-5-(2-carboxychromon- 7-yloxy)pentane (0.25 parts) was crystallised from ethanol and had a melting point between 249 and 251C with preliminary softening.

AnalysIs Found: C, 60.3 H. 4.4% C H O PH O requires: C, 602 H, 4.45%

This acid was dissolved in an equivalent amount of sodium bicarbonate solution and freeze-dried to obtain the disodium salt.

EXAMPLE 18 a. 1,3-Bis( 2-acetyl-3-hydroxy-S-methylphenoxy)-2- hydroxypropane.

To a solution of sodium ethoxide in ethanol (from 0.83 parts of sodium and 20 parts by volume of ethanol) was added a solution of 12 parts of 2,6-dihydroxy- 4-methylacetophenone and 3.34 parts of epichlorohydrin in parts (by volume) of ethanol. The resulting mixture was stirred and refluxed for 4 hrs; after cooling 250 parts of water were added and the solid was isolated by filtration. Crystallisation ofthis solid from ethanol yielded 4.15 parts of l,3-bis(2-acetyl-3-hydroxy- S-methylphenoxy)-2-hydroxypropane melting between 185 and 186C.

Analysis: Found: C. 64.1; H 6.3% C H Q- requires: C. 64.9; H 6.2%

b. 1,3-Bis( 2-carboxy-7-methylchromon-5-yloxy )-2- hydroxypropane By the method of Example 1(b) the above compound was condensed with diethyl oxalate to yield l.3-bis(2- ethoxycarbonyl-7-methylchromon-5-yloxy)-2- hydroxypropane crystallising from ethanol as colourless needles melting between 194 and 196C. The ester was hydrolysed as in Example 5(0) to obtain the acidas the monohydrate crystallising from aqueous dioxan and melting between 240 and 241C.

Analysis: Found: C. 58.3; H. 4.4% C H O H O requires: C. 58.4; H. 4.3%

The acid was subsequently converted to the disodium salt by the method of Example 5(0).

EXAMPLE 19 a. 1.3-Bis( 2-acetyl-4-ethyl-3-hydroxyphenoxy )-2- hydroxypropane 2,6-Dihydroxy-3-ethylacetophenone was condensed with epichlorohydrin by the method of Example 18(a) to yield 1,3-bis(2-acetyl-4-ethyl-3-hydroxyphenoxy)2- hydroxypropane melting between and 137C. (from ethanol).

Analysis: Found: 2:| ..O requires:

b. l,3'Bis(2-carboxy-8-ethy1chromon-S-yloxy )-2- Analysis; Found: C, 57.5; H, 4.9% C H O ZH O requires: C, 57.85; H. 5.0%

The disodium salt was then prepared as in Example 5(0).

EXAMPLE 20 1,3-bis(Z-methylchromon-S-yloxy)propan-Z-ol A stirred suspension of 46 parts of sodium in a solution of 72 parts of l,3-bis(2-acetyl-3- hydroxyphenoxy)-pr0pan'2-0l in 1,000 parts of dry ethyl acetate was heated under reflux for 22.5 hours. 300 parts of chloroform was added to the cooled, yellow reaction mixture followed by cautious addition of a solution of 170 parts of concentrated hydrochloric acid and 900 parts of water. After vigorously stirring the mixture thus produced, the chloroform was separated and the aqueous layer extracted with a further 2 lots of parts of chloroform.

The chloroform extracts were bulked, washed with 2 lots of 150 parts of water, dried over anhydrous sodium sulphate and distilled leaving a red oil which was dissolved in a solution of 400 parts of ethanol and 5 parts of concentrated hydrochloric acid and heated under reflux for 1 hour. Addition of 400 parts of water to the reaction mixture followed by cooling gave 48.2 parts of a pale orange, crystalline solid. This solid was filtered off, washed with a little cold acetone then dissolved in 400 parts of chloroform and chromatographed on 50 parts of activated alumina. Evaporation of the chloroform solution resulting from the alumina treatment gave a light yellow solid which was crystallized from aqueous ethanol (1:1) to give 4l.l parts of l.3-bis(2- methylchromon-S-yloxy)propan-Z-ol as light yellow needles, melting point l48 l49.5.

Found: C. 67.8:

Analysis C ;,H 7 requires: C, 67.6:

EXAMPLE 2] To a stirred suspension of l,5-bis(4-hydroxyphenoxy)pentane (2.7 parts) and maleic anhydride (1 part) in ethylene chloride (350 parts) was added portionwise anhydrous aluminum chloride (3.2 parts). This mixture was stirred at room temperature for 17 hours and then heated with stirring to 80C for 1 hour. After cooling the solid which was obtained was filtered off and decomposed by stirring with crushed ice (50 parts) and concentrated hydrochloric acid (30 parts). On filtering, the crude solid (0.8 parts), l,5-bis-(2- carboxychromanon-6-yloxy)pentane, was isolated and dried. This solid was suspended in amyl alcohol (30 parts) and finely divided selenium dioxide (1.2 parts) was added, then the mixture was heated under reflux for 18 hours. After filtering hot the solution was steam distilled to remove solvent and the l.5-bis(2- carboxychromon-6-yloxy)pentane obtained was purified by dissolving in aqueous sodium bicarbonate and after charcoal treatment was precipitated with dilute hydrochloric acid. The product obtained had m.p.275-277 and was identical with an authentic sample as shown by mixed melting point, IR. spectra and TLC.

The process is shown graphically below:

FORMULA 2 V V O O owHmo w llozclo O/CO2II EXAMPLEZQ O O( C HalaO EXAMPLE 22A A mixture of 15 parts of l,5-bis(2-acetyl-3-hydroxyphenoxy)pentane, parts of toluene, and 35 parts of cinnamoyl chloride were heated under reflux for l2 hours with stirring. The crude product, l,5-bis(2; acetyl-3-cinnamoyloxyphenoxy)pentane, was separated and washed with the solvent. It was heated with powdered potassium hydroxide in pyridine for 15 minutes and the mixture was cooled, diluted with water and acidified with hydrochloric acid. The solid product crystallised from acetic acid to give l,5-bis(2- styrylchromon-S-yloxy)pentane, m.pt. 2l7--220C.

The process is shown graphically below:

FORMULA 4.

O(CH2)5O CHzCO- 000m V HO OH CaH5CH=CHCOC1 CH3C0 0 0 CH;

0 -0 CO CH=CH( J 0 H c xonmo PhCH=CHCOCHzC o- COCHzCOCH=OHPh HO 'OH I rnou=onfi worn-4mm 0 0 EXAMPLE 23 To a solution ofdibromopentane (34 parts) in dry acetone (250 parts) was added potassium carbonate (9.2 parts) and potassium iodide (0.5 parts). The mixture was brought to reflux and a solution of resacetophenone (20 parts) in acetone (100 parts) was added dropwise over a period of one hour. The reaction mixture was heated under reflux for a further 18 hours.

The solution was filtered while hot and the remaining solid washed with hot acetone. The acetone solutions was evaporated to leave an oil which was triturated with ether. The insoluble bisacetophenone was filtered off and the ether solution washed with dilute sodium hydroxide solution, water. dried over magnesium sulphate and evaporated to leave an off-white solid. This was dissolved in ether and chromatographed on a silica column using ether as eluent to give 4-(5- bromopentyloxy)-2-hydroxyacetophenone l3.6 parts) as a colourless solid mp. 64-66C.

Analysis:

Found: ('.52.2; H, 5.81 C,;,H Br();, requires: C, 5l.83; H, 5.65 /1 To a solution of 4-(5-bromopentyloxy)-2- Analysis Found: C. (16.05;

C H O requires: C, 66.07;

i. To an ethanolic solution of sodium ethoxide [from sodium (2.5 parts) in ethanol (30 parts)] and diethyl oxalate (l parts) was added a slurry of ethyl 7-[5-(4- acetyl-3-hydroxyphenoxy)pentyloxylchromone-Z- carboxylate parts) in ethanol (50 parts). This mixture was refluxed with stirring for 4 hours and after cooling. was poured into ether (750 parts). This mixture was then extracted with water (3 X l00 parts); the combined aqueous extracts were acidified and extracted into ethyl acetate (3 X 100 parts). After removal of the ethyl acetate the residual oil was taken up in ethanol (30 parts) to which 1 part of concentrated hydrochloric acid had been added. This solution was refluxed for /2 hour and then allowed to stand over-.

night. The solid which crystallised was filtered off and crystallised from ethanol to yield l,5-bis(2- carboxyethoxychromon-7-yloxy)pentane (1.5 parts), l48-l50. This ester was then hydrolysed in an excess of aqueous sodium bicarbonate on a steam-bath. On acidifying l,5-bis(2-carboxychromon-7- yloxylpentane m.p. 283284C was obtained.

ii. A suspension of ethyl 7-[5-(4-acetyl-3- hydroxyphenoxy)pentyloxy]chromone-2-carboxylate (2 parts) in ethyl acetate (50 parts) was added to powdered sodium (2 parts) and the mixture was heated under reflux for 4 hours with stirring. The solution was cooled, diluted with ether (300 parts) and then ex tracted'with water (3 X 50 parts). The extract was acidified with dilute hydrochloric acid and extracted into chloroform (3 X 60 parts). After drying over anhydrous sodium sulphate the solvent was removed leaving an oil which was taken up in ethanol containing concentrated hydrochloric acid (0.5 parts) and refluxed for l0 minutes. Removal of the solvent left a gummy solid (ethyl- 7-l5-(2-methylchromon-7-yloxy)pentyloxylchromone- 2-carboxylate). This gum was taken up in dioxan (20 parts) and finely divided selenium dioxide (l.3 parts) was added, this mixture was refluxed for 8 hours cooled and the inorganics removed by centrifuging. The solvent was removed by evaporation and the residue was dissolved by heating in aqueous sodium bicarbonate solution. After treating with charcoal, acidification gave l,5-bis( 2-carboxychromon-7-yloxy)pentane.

The processes are shown graphically below:

COCHJ 0 ll l EXAMPLE 24 A mixture of l,5-his(2-ethoxycarhonylehromon-5- yloxy)pentane (3 parts) and ammonia in ethanol (300 parts) (prepared by bubbling ammonia through ethanol with cooling), was stirred at room temperature for 18 hours. Excess of ammonia was boiled off and the remaining precipitate was filtered off after cooling and washed with ethanol. After crystallising from aqueous dimcthyl formamide a white solid (2.3 parts) was obtained, m.p. 2725, comprising l,5-bis( 2- carhamoylchromon-S-yloxy)pentane.

N Found: 63.6; 6 6.0. (QM- N 0,, requires To 500 parts of N,N-dimethylformamide was slowly added 19.3 parts of phosphorus oxychloride with stirring and cooling in ice. Then, in small quantities, 29.9 parts of l,5-bis(2-carbamoylchromon-S-yloxy)pentane was added to the cold solution. After the addition was completed the reaction mixture was stirred at room temperature for 18 hours. The resulting dark solution- 0 crm50 0 I 0 cl n I 2 0 O CO H EXAMPLE 25 To a solution of l0 parts of sodium in l()() parts of ethanol was added a mixture of IO parts of l,5-bis(2- acctyl-3-hydroxyphenoxy)pentane and 150 parts of benzene. followed by 40 parts of ethyl tetrahydropyran-2-yloxyacetate. The mixture was heated under reflux for 6 hours and cooled. It was than poured into a large volume of ether and the precipitated solid was filtered off and washed with ether. It was heated for 1 hour under reflux in 25 parts of glacial acetic acid containing 25 parts ofconcentrated hydrochloric acid. After cooling, the solvent was removed under vacuum and the residual crude l,5-his-(2-hydroxymethylchromon-S- yloxylpentane was dissolved in 50 parts of pyridine and treated with a solution of 10 parts of potassium permanganate in 200 parts of water. Additional quantities of 5 percent potassium permanganate were added as required from time to time. When the oxidation was complete, sulphur dioxide was added to decolourise the mixture. The precipitated material was filtered off, washed with hot water and extracted with sodium bicarbonate solution. On acidification of the alkaline extract the product precipitated and was filtered off, dried and crystallised from ethanol to give l,5-bis(2- carboxychromon-S-yloxy)pentane monohydrate, m.pt. 226228.

The process is shown graphically below:

moment? COOH: 000113 O O (CH2)5O O A l l Hal f) l EXAMPLE 26 A solution of 2.62 parts of l,3-bis(2-ethoxycarbonylchromon-S-yloxy)-2-hydroxypropane in 200 parts of ethanol was reduced. using 1.0 parts of Raney nickel as catalyst, at C under hydrogen at a pressure of 45 lbs/sq. inch. The catalyst was then filtered off and the solvent was evaporated to leave an oil. This oil was crystallised from ether to give 0.5 parts of l,3-bis(2- A mixture ol l,3-bis(2-ethoxycarbonylchromanon-5 yloxyJ-Z-hydroxy-propane (3 parts) and ammonia in ethanol (300 parts) (prepared by bubbling ammonia through ethanol with cooling) was stirred at room temperature for 18 hours. Excess of ammonia was boiled off and the remaining precipitate was filtered off after cooling and washed with ethanol to give the diamide of l 3-bis(2-earboxychromon-5-yloxy)-2 hydroxypropane.

To 500 parts of N,N-dimethylformamide wa slowly added phosphorus oxychloride (20 parts) with stirring and cooling in ice. In small quantities 30 parts of the diamide of l,3-bis(Z-carboxychromanon-S-yloxy)-2- hydroxypropane was added. The mixture was stirred at room temperature for 18 hours, and poured into ice and water. The precipitated solid was filtered off to give the dinitrile of l,3-bis(2-carboxychromanon-5- yloxy)-2-hydroxypropane.

The above dinitrile of l,3-bis(Z-carboxychromanon- 5-yloxy )-2-hydroxypropane was heated in carbon tetrachloride solution with N-bromosuccinimide under reflux for 3 hours. The solution was filtered while still hot to remove insoluble material, then the solution was evaporated and the residue was crystallized from aqueous ethanol to give l,3-bis(2-cyanochromon-5-yloxy)- 2hydroxypropane, the dinitrile of l,3-bis(2- carboxychromon-S-yloxy)-2-hydroxypropane.

The dinitrile of l,3bis(2-carboxychromon5-yloxy)- Z-hydroxy-propane was heated with a mixture of acetic and hydrochloric acids for 18 hours under reflux. The mixture was diluted with water and the resulting solid was filtered offand crystallized from ethanol to give l.- 3-bis( 2-carboxychromon-5-yloxy l-Z-hydroxypropane, m.pt. 2l6-2l7 with decomposition.

The process is shown graphically below:

octigouonoinp o O O CHzGI-IOHCHzO O 0 oomcnonomo p (I) OCHzCHOHCIIzO (I) EXAMPLE 27 A solution of l,3-bis(Z-ethoxycarbonylchromon-5- yloxy)-2-hydroxypropane in ethanol was treated with an excess of potassium borohydride and a few drops of l() percent sodium hydroxide solution. The mixture was allowed to stir for 6 hours. After diluting with water the l,3-hisl2-hydroxymethylchromon-S-yloxy)- Z-hydroxypropane was filtered off.

A solution of l,3-bis(Z-hydroxymethylchromon-S- yloxyJ-Z-hydroxy-propane in ethanol was reduced over a Raney nickel catalyst at C, with hydrogen at a pressure of 45 p.s.i.. The catalyst was filtered off and subsequent evaporation ofthe solvent left the required I,3-bis(Z-hydroxymethylchromanon-5-yloxy)-2- hydroxypropane.

A solution of l,3-bis(2-hydroxymethylchromanon-5- yloxyJ-Z-hydroxy-propane in diosan was heated with an excess of selenium dioxide for 8 hours after reflux. The mixture was cooled and centrifuged to remove the inorganic portion. The solvent was removed by distillation under reduced pressure and the residue was dissolved in sodium bicarbonate solution and filtered. The filtrate was acidified to give l,3-bis(2-carboxychr0man0n-5- yloxy)-2-hydroxypropane monohydrate, as a glassy solid.

A stirred suspension of l,3-bis( 2- carboxychromanon-S-yloxy)-2-hydroxypropane in carbon tetrachloride was heated under reflux for 5 hours with N-bromosuccinimide. The solvent was evaporated and the residue was boiled with water. Insoluble material was filtercd off, washed with water, ethanol, ethyl acetate and dried. it was crystallized from ethanol to give l,3-bis( 2-carboxychromon-5-yloxy )-2- hydroxypropane, melting point, 2l6-l7C with decomposition.

The process is shown graphically below:

O O CHzCHOHCHzO (I) 0 oer-1201101101120 0 35 EXAMPLE 2s A solution of l,5-bis(2-ethoxycarbonylchromon-S- yloxy)pentane in ethanol was treated with excess of potassium borohydride and a few drops of percent sodium hydroxide solution. The mixture was allowed to stir for 6 hours. After dilution with water a precipitate was obtained which was filtered off and dried to give l,5-bis(Z-hydroxymethylchromon-S-yloxy)pentane.

A solution of l,5-bis(2-hydroxymethylehromon-5- yloxy)-pentane in ethanol was reduced over a Raney nickel catalyst at 80C with hydrogen at a pressure of 45 p.s.i.. The catalyst was filtered off and. following removal of the solvent. there remained l.5-bis(2- hydroxymethylchromanon-5-yloxy)pentane.

A solution of l,5-bis(2-hydroxymethylchromanon-S- yloxy)pentane in dioxan was heated with an excess of selenium dioxide for 8 hours after reflux. The mixture was cooled and inorganic material was removed by centrifuge and decantation. The solvent was evaporated under reduced pressure and the residue was extracted with sodium bicarbonate solution. The bicarbonate extract was filtered, then acidified to give 1,5-

bis(2-carboxychromanon-5-yloxy)pentane, melting point, 76-8C.

EXAMPLE 29 A solution of 1.35 parts of l,5-bis(2- ethoxycarbonylchromon-S-yloxy)pentane in 180 parts of ethanol was reduced over a Raney nickel catalyst at 80 in a hydrogen atmosphere at 45 psi. during a 6 hours period. The catalyst was filtered off and solvent was removed. The residual oil was crystallized from ethanol to give 0.73 parts of l,5-bis(2- ethoxycarbonylchromanon-5-yloxy)pentane, melting point 1 l23C.

Analysis:

Found: C. 64.l; C H- O requires: C. 64.43;

A stirred suspension of l .5-bis( 2- ethoxycarbonylchromanon-5-yloxy)pentane in a solution of ethanolic ammonia was stirred at room temperature for 18 hours. The ammonia was then boiled off and the solvent evaporated to leave the diamide of 1,5- bis(Z-carboxychromanon-5-yloxy)pentane.

To 500 parts of N,N-dimethylformamide was slowly added 20 parts of phosphorus oxychloride with stirring and cooling at 0C. To the solution was added, in small quantities, parts of the diamide of l,5-bis(2- carboxychromanon-S-yloxy)pentane. The mixture was stirred at room temperature for 18 hours then it was poured into ice-water. Precipitated material was filtered off and dried to give the dinitrile of l,5-bis(2- carboxychromanon-S-yloxy)pentane.

The dinitrile of l,5-bis(2-carboxychromanon-5- yloxy)-pentane was heated in carbon tetrachloride solution with A stirred suspension of l,5-bis( 2- carboxychromanon-S-yloxy)pentane in carbon tetrachloride was heated under reflux for 5 hours with N- bromosuccinimide. The solvent was then evaporated and the residue was boiled with water. lnsoluble material was filtered off and was washed successively with water, ethanol, and finally ethyl acetate then dried to give l,S-bist2-carboxychromon-5-yloxy)pentane, melt- 36 ing point, 226-228C after crystallization from ethanol. y The process is shown graphically below:

0 o H I H i q V lH V oom N-bromosuccinimide under reflux for 3 hours. The solution was filtered while still hot to remove insoluble material, then the solution was evaporated and the residue was crystallized from aqueous ethanol to give the dinitrile of l,5-bis( 2-carboxychromon-S-yloxy pentane, melting point l92-l95C.

The dinitrile of l,5-bis(2-carboxychromon-5-yloxy)- pentane was heated with a mixture of aqueous acetic and hydrochloric acids for 18 hours after reflux. The solvent was removed and the residue was washed with water and crystallized from ethanol to give l,5-bis(2- carboxychromon-S-yloxy)pentane, melting point 226-8C.

The process is shown graphically below:

EXAMPLE 3O l.3-bis( 2-styryleromon-S-yloxy)Z-hydroxypropane To a solution of 4.1 parts of 1,3-bis(2- methylchromon-S-yloxyl-2-hydroxypropane dissolved in a solution of sodium ethoxide, prepared from 0.46 parts of sodium and 50 parts by volume of ethanol, was added dropwise, 1.92 parts of benzaldehyde. The resulting chcrry-red solution was then set aside at ambient temperature for 65 hours during which time a yellow solid slowly precipitated from the solution.

The resulting mixture was diluted with 200 parts of water and extracted with 3 lots of 150 parts of chloroform. The chloroform extracts were bulked, washed with water until the washings were neutral, dried over anhydrous sodium sulphate, and then distilled giving a yellow solid. Crystallisation of this solid from chloroform/ethanol yielded 3.1 parts of l,3-bis(2-styrylchromon-5-yloxy)-2-hydroxypropane as a light-yellow, amorphous solid, melting point 2l4-2l5.

Found: C, 76.4:

EXAMPLE 31 l,3-bis(Z-methylchromon-S-yloxy)-2-hydroxypropane 23.5 parts of sodium were pulverised in 500 parts of xylene. The xylene was then decanted and the sodium powder washed by successive decantations with dry ether. To the sodium was added a suspension of 36 parts of l,3-bis( Z-acetyl-3-hydroxyphen0xy)-2- hydroxypropane in 500 parts of ethyl acetate. The mixture was stirred under reflux for 2.5 hours, and then half the ethyl acetate was evaporated leaving a thick yellow precipitate. This was filtered off, washed with ether, and dissolved in water to give a deep red solution. This was acidified with glacial acetic acid to precipitate a semisolid oil. The supernatent liquors were decanted off and the oil was dissolved in 100 parts of ethanol containing 2 parts concentrated hydrochloric acid. The solution was charcoaled, filtered, and stored at 0 overnight to give pale yellow crystals which were filtered off, washed with petroleum ether, b.pt. 40-60, and dried at 60. There were obtained 17.8

EXAMPLE 32 The activity of the new bis chromonyl compounds has been evaluated by the antigen inhalation test on human volunteers who suffer from specific allergic asthma. The degree of asthma provoked by the inhalation of an antigen to which the volunteers are sensitive can be measured by repeated estimation ofthe increase of air-way resistance.

A suitably designed spirometer was used to measure the forced expiratory volume at one second (F.E.V. and hence the changes in the air way resistance. The anti-allergic activity of a compound is estimated from the difference between the maximum per cent F.E.V., reduction following control and test provocations after drug administration conducted under identical experimental conditions.

Thus:

% protection 100 X [(Av. maxf/l F.E.V., fall control sh0ck/Av.max/( F.E.V., ,,).(MaX./( F.E.V.l.() fall test shock/fall control shoekl] The compounds under test were administered as an aerosol by inhalation for five minutes, two hours before challenge with antigen. The compounds for administration were dissolved in sterile water at a concentration of 0.5 percent and aerosolized from a Wright nebulizer operating at 10 litres/minute air flow, giving a total weight of drug aerosolized of 5 mg. The following table shows the protection obtained with a number of the new bis-chromonyl compounds.

Compound Under Test '74. Protection Disodium salt of 30 35 1,5-hist Z-earboxychn mon-5yloxy)-pentane. Disodium salt of l,7-bis( Z-carboxychromon-5-yloxy)-2,6-dihy droxy-4-oxaheptane.

Disodium salt of l,4-bis( l-carboxychromon-S-yloxy)hutane. Disodium salt of 1,4-hist 2-carboxychromon-5-yloxy)-2,3- dihydroxybutane.

Disodium salt of l,4-bis( Z-carboxychromon-S-yloxy J-Z-hydroxybutane.

Disodium salt of l.4-his( 2-carboxychromon-S-yloxy rhut-Z-enc. Disodium salt of 1,l0-bis( 2-carboxychromon-S-yloxy )-decane. Disodium salt of l,6-his( Z-carhoxychromon5-yloxy l-hexane. Disodium salt of l,3-bis( 2-earboxychromon-S-yloxy)-2- hydroxypropane.

Disodium salt of 1.3-bist Z-carboxychromon-S-yloxy)-propane. Disodium salt of l.5-his( Z-CarhoXy-X-ehIoro-chromon-S- yloxyjpentane.

Disodium salt of l.5-bist 2-carboxychromon-fv-yloxy )-pentane. Disodium salt of l.5-bis( Z-carhoxychromon-7-yloxy l-pentane. Disodium salt of l ,3-bis( 2-carboxyehromon-7yloxy)-2- hydroxypropane.

Disodium salt of l.3-bis( Z-earboxy X-ethyl-ehro|non-5-yloxy )-2- hydroxypropane.

Disodium salt of 1,2-hist Z-carhoxychromon-S-yloxymethyl benzene.

Disodium salt of l-( Z-carboxychromon-S-yloxy J-3-t 2- carboxychromon-7-yloxy )-2-hyd roxypropane. Disodium salt of l,3-bis( 2-carboxychromon-(w-yloxy J-2- hydroxypropane.

Disodium salt of l,3-hist2'carboxy-8methylchromon-7-yloxy)-2- hydroxypropant:v

Disodium salt of l-(2-carboxychromon-S-yloxy)-3(2-carboxy-8- 

1. A COMPOUND OF THE FORMULA OR A THERAPEUTICALLY ACCEPTABLE SALT, ESTER OR AMIDE THEREOF.
 2. A compound of the formula
 3. A compound of the formula
 4. A compound of the formula 